rs1064796675
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The NM_005993.5(TBCD):c.880C>T(p.Arg294Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005993.5 missense
Scores
Clinical Significance
Conservation
Publications
- early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000809 AC: 2AN: 247086 AF XY: 0.00000744 show subpopulations
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1459668Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 726160 show subpopulations
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74282 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
The R294W variant in the TBCD gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R294W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R294W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R294W as a variant of uncertain significance. -
This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 294 of the TBCD protein (p.Arg294Trp). This missense change has been observed in individual(s) with progressive early-onset encephalopathy with brain atrophy and thin corpus callosum (PMID: 32705489). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TBCD protein function. ClinVar contains an entry for this variant (Variation ID: 423874). -
not specified Uncertain:1
Variant summary: TBCD c.880C>T (p.Arg294Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. The variant allele was found at a frequency of 8.1e-06 in 247086 control chromosomes (gnomAD). c.880C>T has been observed in 2 compound heterozygous individuals affected with Encephalopathy, Early Onset (Isik_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32705489). ClinVar contains an entry for this variant (Variation ID: 423874). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at